Carbon monoxide (CO) is a colorless, odorless, tasteless, non-corrosive gas of about the same density of air. It is well known that carbon monoxide gas is poisonous in high concentrations. Like nitric oxide (NO), carbon monoxide is an important, yet only recently recognized biological signaling molecule, as is described, for example, by M. K. Choi, L. E. Otterbein (eds.), Antioxidants & Redox signaling, 4, pp 227-338 (2002). It has also been suggested that carbon monoxide acts as a neuronal messenger molecule in the brain and as a neuro-endocrine modulator in the hypothalamus. Like nitric oxide, carbon monoxide is also a smooth muscle relaxant and inhibits platelet aggregation.
Carbon monoxide is constantly produced in small doses in the human body in the course of heme degradation by the heme-oxygenase (HO) enzymes. Carbon monoxide exhibits cytoprotective, anti-inflammatory, vasodilatory and other effects, which are of importance, for instance, in our body's response to injuries as described, for example, in S. W. Ryter, J. Alam, A. M. K. Choi: Physiol. Rev., 86, pp 583-650 (2006). Despite these beneficial biological properties, the application of carbon monoxide as a therapeutic agent has only recently garnered attention. The application of carbon monoxide as a therapeutic agent is described in various patents and in the literature.
WO 03/000114 A2 describes the use of carbon monoxide as a gas, liquid or dissolved in aqueous solution to promote the survival and function of organ, tissue and individual cell transplants. The carbon monoxide can thereby be delivered via inhalation, intravenously or via perfusion through the blood vessels of an organ or tissue. WO 03/094932 A1 and U.S. Pat. No. 7,678,390 B2 describe the use of carbon monoxide as a biomarker and therapeutic agent of heart, lung, liver, spleen, brain, skin and kidney diseases and other conditions and disease states including, for example, asthma, emphysema, bronchitis, adult respiratory distress syndrome, sepsis, cystic fibrosis, pneumonia, interstitial lung diseases, idiopathic pulmonary diseases, other lung diseases including primary pulmonary hypertension, secondary pulmonary hypertension, cancers, including lung, larynx and throat cancer, arthritis, wound healing, Parkinson's disease, Alzheimer's disease, peripheral vascular disease and pulmonary vascular thrombotic diseases such as pulmonary embolism. The use of carbon monoxide is also described to provide anti-inflammatory relief in patients suffering from oxidative stress and other conditions especially including sepsis and septic shock and as a biomarker or therapeutic agent for reducing respiratory distress in lung transplant patients and to reduce or inhibit oxidative stress and inflammation in transplant patients. U.S. Pat. No. 7,678,390 B2 thereby describes the delivery of carbon monoxide as a gaseous composition while WO 03/094932 A1 describes delivery in both gaseous and liquid form.
U.S. Pat. No. 7,238,469 B2 describes the administration of carbon monoxide to enhance the survival of cells following transplantation. The carbon monoxide is thereby administered as a gas, liquid or as a composition.
The use of gaseous carbon monoxide is risky and is strongly limited by the high affinity of carbon monoxide towards hemoglobin and the resulting systemic effects on oxygen transport and low bioavailability. This affinity to bind to hemoglobin in the blood stream rapidly decreases the oxygen transport capability of the cardiovascular system.
A strategy to circumvent these problems and to deliver controlled amounts of carbon monoxide directly to a tissue is the use of carbon monoxide-releasing molecules (so called CORMs). Roberto A. Motterlini has identified a series of transition-metal carbonyl complexes fulfilling this function as is described, for example, in R. Motterlini, B. E. Mann, T. R. Johnson, J. E. Clark, R. Foresti, C. J. Green: Curr. Pharm. Design, 9, pp 2525-2539 (2003); B. E. Mann, R. Motterlini, Chem. Commun., pp 4197-4208 (2007); R. Alberto, R. Motterlini: Dalton Trans., pp 1651-1660 (2007); and in R. Motterlini, L. E. Otterbein, NatureRev. Drug Discov., 9, pp 728-743 (2010). The first CORMs, such as Mn2(CO)10, required UV activation. The dinuclear Ru-complex 1 (CORM-2), having the formula
liberates carbon monoxide upon ligand exchange with dimethyl sulfoxide (DMSO).
The related mononuclear glycinato complex 2 (CORM-3) having the formula
has better solubility in water and releases carbon monoxide under physiological conditions as described, for example, by T. R. Johnson, B. E. Mann, I. P. Teasdale, H. Adams, R. Foresti, C. J. Green, R. Motterlini: Dalton Trans., pp 1500-1508 (2007).
Existing CORM compounds suffer from serious limitations. For example, the carbon monoxide release from CORM 3 is very fast (t1/2≈1 min) and unspecific as is described by R. Motterlini, B. E. Mann, R. Foresti: Expert. Opin. Investig. Drugs, 14, pp 1305-1318 (2005). This hampers the delivery of controlled amounts of carbon monoxide to a target tissue.
Various approaches have been suggested to overcome this problem. For example, R. Foresti, M. G. Bani-Hani, R. Motterlini: Intensive Care Med., 34, pp 649-658 (2008) describes the use of stable molecules as precursors which are then converted into CORMs by means of a trigger. One such possible trigger is pH which leads to a pH-dependent carbon monoxide liberation from a boranocarbonate as described by R. Motterlini, P. Sawle, J. Hammad, S. Bains, R. Alberto, R. Foresti, C. J. Green: FASEB, 19, pp 284-286 (2005) or from amino derivatives of boranocarbonates as is described in T. S. Pitchumony, B. Spingler, R. Motterlini, R. Alberto: Org. Biomol. Chem., 8, pp 4849-4854 (2010). Another approach is the photo-induced carbon monoxide release of transition-metal carbonyl complexes of UV-absorbing organic ligands. This approach is described, for example, in J. Niesel, A. Pinto, H. W. Peindy N'Dongo, K. Merz, I. Ott, R. Gust, U. Schatzschneider: Chem. Commun., pp 1798-1800 (2008); H. Pfeiffer, A. Rojas, J. Niesel, U. Schatzschneider: Dalton Trans., pp 4292-4298 (2009); R. D. Rimmer, H. Richter, P. C. Ford: Inorg. Chem., 49, pp 1180-1185 (2010); and in U. Schatzschneider: Eur. J. Inorg. Chem., pp 1451-1467 (2010).
The patent literature also describes various CORMs and releasing mechanisms. U.S. Pat. No. 7,011,854 B2, US 2006/0148900 A1 and US 2006/0233890 A 1 describe CORMs and a method for treating a mammal by administration thereof. The preferred CORMs comprise two components, a carbon monoxide releasing moiety, and a second pharmaceutically important molecule, such as a known drug carrier, and/or a known anti-inflammatory agent. A preferred class of conjugation partners for the carbon monoxide-donors include nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin and anti-inflammatory agents, such as steroids and inhibitors of phosphodiesterases (PDE), such as inhibitors of PDE4. US 2006/0148900 A1 thereby concentrates on organic substances while US 2006/0233890 A1 seeks to disclaim CORMs which include, for example, an Fe or Ru complex. Release of carbon monoxide occurs either spontaneously or by a metabolic process involving one or more enzymes. Release mechanisms for spontaneous release include thermal, chemical, oxydatively induced release and release by reactions induced by light. Enzymes for metabolic process release can include, for example, cytochrome P450 and glutathione S-transferase.
US 2007/0207217 A1 describes molybdenum carbonyl CORM complexes useful for inhibiting tumor necrosis factor (TNF) production and for treating inflammatory diseases. Release mechanisms for the molybdenum carbonyl CORM complexes include both spontaneous release means and release by metabolic process means via the involvement of one or more enzymes.
None of U.S. Pat. No. 7,011,854 B2, US 2006/0148900 A1, US 2006/0233890 A1 and US 2007/020717 A1 provide a proof of concept of how a CORM can release carbon monoxide using an enzyme as a trigger. Each of U.S. Pat. No. 7,011,854 B2, US 2006/0148900 A1 and US 2006/0233890 A1 merely describe that certain organic substances, such as polyhalomethanes, produce dichlorocarbene which, under physiological conditions, will in turn be metabolized to carbon monoxide.
U.S. Pat. No. 7,045,140 B2 describes metal carbonyl CORMs to deliver carbon monoxide. The described CORMs typically have Ru or Fe as the complexing metal, whereby Fe is combined with a cyclopentadiene, and preferably has one or more ligands other than carbon monoxide, such as an amino acid. Various release mechanisms such as dissociation of the metal carbonyl, contact with a solvent, contact with a tissue organ or cell, and via irradiation are described. US 2007/0065485 A1 describes boranocarbonate CORMs which can be administered with a guanylate cyclase stimulate or stabilizer. US 2006/0127501 A1 describes metal carbonyls as CORMs to deliver carbon monoxide to limit post-ischaemic damage. The majority of the specifically disclosed CORMs contain ruthenium as the complexing metal and preferably contain one or more other ligands apart from carbon monoxide such as amino acids. US 2006/0147548 A1 describes CORMs comprising metal carbonyls used in combination with at least one guanylate cyclase stimulate or stabilizer. The majority of the specifically disclosed CORMs contain ruthenium as the complexing metal. WO 2007/085806 A2 describes CORMs that employ transition metal complexes having at least a substituted cyclopentadenyl, indenyl or fluorenyl ligand and two or more carbonyl ligands. US 2010/0105770 A1 describes CORMs comprising Mn complexes having carbon monoxide ligands which can be used for the therapeutic delivery of carbon monoxide.
None of the CORMs described to date have provided a satisfactory solution for the target-specific release of carbon monoxide.